7. Project Summary/Abstract Consumption of fish is a major source of exposure to environmental contaminants for the general population, including persistent organic pollutants such as polychlorinated biphenyls (PCBs), p,p?-diphenyldichloroethene (DDE), polybrominated diphenyl ethers (PBDEs) and perfluoroalkyl substances (PFAS), as well as metals such as methyl mercury (meHg). Exposure to these pollutants may cause dysregulation of endocrine function, affecting steroid and thyroid hormones as well as glucose and lipid metabolism. To date, few studies have evaluated the impact of multiple contaminants found in fish on endocrine function, and even fewer have considered that the harmful effects of contaminants in fish may be counterbalanced by beneficial nutrients such as selenium and iodide. The Great Lakes Fish Consumer Study (GLFCS) is an ongoing longitudinal study of both frequent and infrequent consumers of sport fish. In this population, we have previously demonstrated associations of PCBs, PBDEs, DDE and/or fish consumption with various endocrine endpoints, including increased diabetes incidence and changes in hemoglobin A1c, thyroid hormones, thyroid autoantibodies, steroid hormones and hormone binding proteins. We propose to leverage this unique, well characterized cohort to measure additional contaminant exposures and nutrients, namely PFAS, Hg, and selenium, in banked biosamples from 490 study participants. Specifically, we will (1) determine if key measures of endocrine function in the GLFCS cohort are associated with exposure to PFAS and mercury individually and in mixed exposures with PCBs, DDE and PBDEs; and (2) investigate if levels of serum selenium and urinary iodide impact associations of endocrine function with PFAS, mercury, PCBs, DDE and PBDEs. We will also explore associations of mercury and PFAS on self-reported incident and prevalent endocrine disease, including diabetes, hypothyroidism and hyperlipidemia.Currently available exposure and nutrient measurements include serum PCBs, DDE, and PBDEs, urinary iodide, and estimated mercury intake from reported fish consumption. Currently available outcome measurements include self-reported diabetes, prediabetes, hypothyroidism; thyroid hormones, sex steroid hormones, gonadotropins, hormone binding proteins, autoantibodies and markers of glucose and lipid homeostasis. We will use both standard (linear, logistic and Cox proportional hazards regression models) and alternative (elastic net; propensity score adjustment; weighted quantile sum regression) analytic approaches to evaluate associations of individual chemicals and mixtures of contaminants with markers of endocrine dysregulation. This investigation is expected to lead to a better understanding of the effects of pollutants on endocrine function and disease in adults, which will guide advice to consumers on the risks and benefits of fish consumption.